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Distinct Molecular Trajectories Converge to Induce Naive Pluripotency.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Stuart, Hannah T 
Stirparo, Giuliano G 
Lohoff, Tim 
Bates, Lawrence E 

Abstract

Understanding how cell identity transitions occur and whether there are multiple paths between the same beginning and end states are questions of wide interest. Here we show that acquisition of naive pluripotency can follow transcriptionally and mechanistically distinct routes. Starting from post-implantation epiblast stem cells (EpiSCs), one route advances through a mesodermal state prior to naive pluripotency induction, whereas another transiently resembles the early inner cell mass and correspondingly gains greater developmental potency. These routes utilize distinct signaling networks and transcription factors but subsequently converge on the same naive endpoint, showing surprising flexibility in mechanisms underlying identity transitions and suggesting that naive pluripotency is a multidimensional attractor state. These route differences are reconciled by precise expression of Oct4 as a unifying, essential, and sufficient feature. We propose that fine-tuned regulation of this "transition factor" underpins multidimensional access to naive pluripotency, offering a conceptual framework for understanding cell identity transitions.

Description

Keywords

cell identity transitions, pluripotency, reprogramming, signaling, transcriptional networks, Animals, Blastocyst Inner Cell Mass, Cell Differentiation, Cell Line, Cell Plasticity, Cellular Reprogramming, Female, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Germ Layers, Mice, Mice, Inbred C57BL, Octamer Transcription Factor-3, Pluripotent Stem Cells, Signal Transduction

Journal Title

Cell Stem Cell

Conference Name

Journal ISSN

1934-5909
1875-9777

Volume Title

25

Publisher

Elsevier BV
Sponsorship
Wellcome Trust (101861/Z/13/Z)
Wellcome Trust (097922/Z/11/Z)
Wellcome Trust (105031/D/14/Z)
Medical Research Council (MR/R017735/1)
Medical Research Council (MC_PC_12009)
Biotechnology and Biological Sciences Research Council (BB/M004023/1)
Biotechnology and Biological Sciences Research Council (BB/P009867/1)
Biotechnology and Biological Sciences Research Council (BB/R018588/1)
HTS is funded by MRC PhD Studentship 1233706, JCRS by Wellcome Fellowship WT101861, and BG by Bloodwise, CRUK, Wellcome and NIH-NIDDK. The authors gratefully acknowledge core support from the Wellcome-MRC Cambridge Stem Cell Institute.